In the brain, the innate immune response is initiated by microglia and amplified by astrocytes, which through glial communication act to propagate the neuroinflammatory response. It is well known that adenosinergic signaling is ubiquitous to the brain yet is immerging as a key regulatory mechanism that can be utilized to disrupt neuroglial communication and reduce neuroinflammation. Both microglia and astrocytes possess adenosinergic receptors and express the enzymes that metabolize extracellular ATP and adenosine which in turn modulate adenosinergic and inflammatory signaling. Because adenosine can influence neuronal activity and modulate neuroinflammation, being able to modulate adenosine levels or the receptors involved in adenosinergic signaling has a broad therapeutic potential. However, the link between acetate-induced epigenetic changes in purinergic protein expression is not well understood. Based on these studies we propose the hypothesis that increasing acetate metabolism, via increases in histone acetylation, will modulate purinergic signaling in microglia promoting an anti-inflammatory phenotype. To test this hypothesis we will complete following two aims (1) to determine the mechanism(s) by which acetate alters purine metabolism and (2) to determine the functional effect that acetate-induced changes in purinergic signaling have on inflammatory phenotype. Our working hypothesis is that acetate-induced changes in purinergic signaling will confer an anti-inflammatory phenotype my modulating histone acetylation. By describing how energy supplementation can influence the expression of enzymes and receptors involved in purinergic signaling is important to understand the therapeutic mechanism of acetate supplementation. The innovative of this study is to determine the epigenetic link between an increase in acetyl-CoA metabolism, alterations in purinergic signaling, and its functional effect on inflammatory phenotype.